The histamine H4 receptor (H4R), sometimes also referred to simply as “H4” or “H4”, is the most recently identified receptor for histamine (for reviews, see: Fung-Leung, W.-P., et al., Curr. Opin. Invest. Drugs 2004, 5(11), 1174-1183; de Esch, I. J. P., et al., Trends Pharmacol. Sci. 2005, 26(9), 462-469; Zhang, M. et al. Pharmacol. Ther. 2007, 113, 594-606; Thurmond, R. L. et al. Nat. Rev. Drug Disc. 2008, 7, 41-53; Zhang, M. et al. Expert Opin. Investig. Drugs 2006, 15(11), 1443-1452). The receptor is found in the bone marrow and spleen and is expressed on eosinophils, basophils, mast cells (Liu, C., et al., Mol. Pharmacol. 2001, 59(3), 420-426; Morse, K. L., et al., J. Pharmacol. Exp. Ther. 2001, 296(3), 1058-1066; Hofstra, C. L., et al., J. Pharmacol. Exp. Ther. 2003, 305(3), 1212-1221; Lippert, U., et al., J. Invest. Dermatol. 2004, 123(1), 116-123; Voehringer, D., et al., Immunity 2004, 20(3), 267-277), CD8+ T cells (Gantner, F., et al., J. Pharmacol. Exp. Ther. 2002, 303(1), 300-307), dendritic cells, and human synovial cells from rheumatoid arthritis patients (Ikawa, Y., et al., Biol. Pharm. Bull. 2005, 28(10), 2016-2018). The histamine H4 receptor is also elevated in human nasal polyp tissue (Jókúti, A. et al. Cell. Biol. Int. 2007, 31, 1367-1370). However, expression in neutrophils and monocytes is less well defined (Ling, P., et al., Br. J. Pharmacol. 2004, 142(1), 161-171; Damaj, B. B. et al. J. Immunol. 2007, 179, 7907-7915). Receptor expression is at least in part controlled by various inflammatory stimuli (Coge, F., et al., Biochem. Biophys. Res. Commun. 2001, 284(2), 301-309; Morse, et al., 2001), thus supporting that H4 receptor activation influences inflammatory responses. Because of its preferential expression on immunocompetent cells, the H4 receptor is closely related with the regulatory functions of histamine during the immune response.
A biological activity of histamine in the context of immunology and autoimmune diseases is closely related with the allergic response and its deleterious effects, such as inflammation. Events that elicit the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection, and invasion by a foreign body. The inflammatory response is characterized by pain, increased temperature, redness, swelling, reduced function, or a combination of these.
Mast cell degranulation (exocytosis) releases histamine and leads to an inflammatory response that may be initially characterized by a histamine-modulated wheal and flare reaction. A wide variety of immunological stimuli (e.g., allergens or antibodies) and non-immunological (e.g., chemical) stimuli may cause the activation, recruitment, and de-granulation of mast cells. Mast cell activation initiates allergic inflammatory responses, which in turn cause the recruitment of other effector cells that further contribute to the inflammatory response. It has been shown that histamine induces chemotaxis of mouse mast cells (Hofstra, et al., 2003). Chemotaxis does not occur using mast cells derived from H4 receptor knockout mice. Furthermore, the response is blocked by an H4-specific antagonist, but not by H1, H2 or H3 receptor antagonists (Hofstra, et al., 2003; Thurmond, R. L., et al., J. Pharmacol. Exp. Ther. 2004, 309(1), 404-413). The in vivo migration of mast cells to histamine has also been investigated and shown to be H4 receptor dependent (Thurmond, et al., 2004). The migration of mast cells may play a role in allergic rhinitis and allergy where increases in mast cell number are found (Kirby, J. G., et al., Am. Rev. Respir. Dis. 1987, 136(2), 379-383; Crimi, E., et al., Am. Rev. Respir. Dis. 1991, 144(6), 1282-1286; Amin, K., et al., Am. J. Resp. Crit. Care Med. 2000, 162(6), 2295-2301; Gauvreau, G. M., et al., Am. J. Resp. Crit. Care Med. 2000, 161(5), 1473-1478; Kassel, O., et al., Clin. Exp. Allergy 2001, 31(9), 1432-1440). In addition, it is known that in response to allergens there is a redistribution of mast cells to the epithelial lining of the nasal mucosa (Fokkens, W. J., et al., Clin. Exp. Allergy 1992, 22(7), 701-710; Slater, A., et al., J. Laryngol. Otol. 1996, 110, 929-933). These results show that the chemotactic response of mast cells to histamine is mediated by histamine H4 receptors.
It has been shown that eosinophils can chemotax towards histamine (O'Reilly, M., et al., J. Recept. Signal Transduction 2002, 22(1-4), 431-448; Buckland, K. F., et al., Br. J. Pharmacol. 2003, 140(6), 1117-1127; Ling et al., 2004). Using H4 selective ligands, it has been shown that histamine-induced chemotaxis of eosinophils is mediated through the H4 receptor (Buckland, et al., 2003; Ling et al., 2004). Cell surface expression of adhesion molecules CD11b/CD18 (LFA-1) and CD54 (ICAM-1) on eosinophils increases after histamine treatment (Ling, et al., 2004). This increase is blocked by H4 receptor antagonists but not by H1, H2, or H3 receptor antagonists.
The H4R also plays a role in dendritic cells and T cells. In human monocyte-derived dendritic cells, H4R stimulation suppresses IL-12p70 production and drives histamine-mediated chemotaxis (Gutzmer, R., et al., J. Immunol. 2005, 174(9), 5224-5232). A role for the H4 receptor in CD8+ T cells has also been reported. Gantner, et al., (2002) showed that both H4 and H2 receptors control histamine-induced IL-16 release from human CD8+ T cells. IL-16 is found in the bronchoalveolar fluid of allergen- or histamine-challenged asthmatics (Mashikian, V. M., et al., J. Allergy Clin. Immunol. 1998, 101 (6, Part 1), 786-792; Krug, N., et al., Am. J. Resp. Crit. Care Med. 2000, 162(1), 105-111) and is considered important in CD4+ cell migration. The activity of the receptor in these cell types indicates an important role in adaptive immune responses such as those active in autoimmune diseases.
In vivo H4 receptor antagonists were able to block neutrophillia in zymosan-induced peritonitis or pleurisy models (Takeshita, K., et al., J. Pharmacol. Exp. Ther. 2003, 307(3), 1072-1078; Thurmond, et al., 2004). In addition, H4 receptor antagonists have activity in a widely used and well-characterized model of colitis (Varga, C., et al., Eur. J. Pharmacol. 2005, 522(1-3), 130-138). These results support the conclusion that H4 receptor antagonists have the capacity to be anti-inflammatory in vivo.
Another physiological role of histamine is as a mediator of itch and H1 receptor antagonists are not completely effective in the clinic. Recently, the H4 receptor has also been implicated in histamine-induced scratching in mice (Bell, J. K., et al., Br. J. Pharmacol. 2004, 142(2), 374-380). The effects of histamine could be blocked by H4 antagonists. These results support the hypothesis that the H4 receptor is involved in histamine-induced itch and that H4 receptor antagonists will therefore have positive effects in treating pruritis. Histamine H4 receptor antagonists have been shown to attenuate experimental pruritis (Dunford, P. J. et al. J. Allergy Clin. Immunol. 2007, 119(1), 176-183).
Modulation of H4 receptors controls the release of inflammatory mediators and inhibits leukocyte recruitment, thus providing the ability to prevent and/or treat H4-mediated diseases and conditions, including the deleterious effects of allergic responses such as inflammation. Compounds according to the present invention have H4 receptor modulating properties. Compounds according to the present invention have leukocyte recruitment inhibiting properties. Compounds according to the present invention have anti-inflammatory properties. Modulation of the histamine H4 receptor has also been implicated in the treatment of pain (Intl. Pat. Appl. Publ. WO 2008/060766 (Abbott).
Numerous pro-inflammatory cytokines have been increasingly reported to be elevated in patients suffering of major depression (Frommberger et al., European Archives of Psychiatry & Clinical Neuroscience. 1997, 247(4), 228-33; Sluzewska A., et al., Psychiatry Research, 1996, 64(3), 161-7; Ortiz-Dominguez, et al., Bip. Disporder 9, 2007; O'Brien, et al., J. Affective Disorders, 2006, 90, 263-267; Anisman H. et al., Biological Psychiatry, 1999, 46(12), 1649-55) (when compared with non-depressed subjects or, in some cases, correlated with symptom severity). These include increased acute-phase proteins (Kling et al., Biol. Phychiatry, 2007, 62, 309-313; Kim et al., Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2007, 31, 1044-1053; (C-reactive protein, α-1-acid glycoprotein, α-1-antichymotrypsin and haptoglobin), increased expression of chemokines and adhesion molecules (including human macrophage chemoattractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1) and E-selectin), increased serum and/or plasma concentrations of interleukin (IL-1-β, IL-6, and tumor necrosis factor (TNF)-α, both in the peripheral blood circulation and in the central nervous system (particularly in the cerebrospinal fluid) with a higher level of consistency when measuring TNF-α and IL-6 (O'Brien et al., Journal of Psychiatric Research, 2007, 41, 326-331; Moorman et al., J. of Cardiac Failure, 2007, 13(9), 738-43; Soygur et al., Progress in Neuro-Psychopharmacology & Biolofical Psychiatry, 2007, 31, 1242-1247). Additionally, allelic variants of the genes for IL-1β and TNF-α increase the risk for depression and are associated with reduced responsiveness to antidepressant therapy. Finally, there is available preclinical evidence supporting the involvement of several cytokines in models of depression and some clinical evidence of the involvement of cytokines antagonism in the treatment of depressive symptoms on patients suffering from active inflammatory diseases (Kim et al., Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2007, 31, 1044-1053).
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine (U.S. Pat. No. 7,507,737, Example 2) is a potent antagonist of the H4 receptor (H4R) with a Ki of 8.4 nM and greater than 25-fold selectivity over other histamine receptors in vitro. It inhibited histamine-induced shape change of eosinophils, chemotaxis of mast cells, and IL-6 production in mast cells. In vivo, [5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine reduced inflammation in mouse models of asthma, arthritis and dermatitis. The compound also inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production and other cytokines in vivo.
Based on this the evidence and the effects of H4R antagonism it is proposed that [5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine and its chemically related family of compounds has antidepressant and/or anxiolytic properties suitable for the treatment of mood disorders (including but not limited to Major Depressive Disorder, Bipolar Disorder, Treatment Resistant Major Depressive Disorder and Treatment Resistant Bipolar Disorder), anxiety disorders (including but not limited to Generalized Anxiety Disorder, Social Phobia, and post traumatic stress disorder). It is envisaged that H4 antagonists will share such properties suitable for the treatment of such disorders.
Adiposity-associated inflammation and insulin resistance are associated with the development of type II diabetes, fatty liver and atherosclerosis. Macrophages are recruited into adipose tissue and atherosclerotic plaques, and are activated to release inflammatory cytokines and chemokines. High fat diets associated with the development of these conditions may lead to increased gut permeability and dyslipidemia. Consequent toll-ligand receptor, 2 and 4 (TLR2, TLR4) activation of adipocytes and macrophages by bacteria and by high levels of free fatty acids leads to an inflammatory phenotype and insulin resistance. Specifically, insulin signaling pathways may be attenuated by cytokines such as TNFα and IL-6 and activation of kinases including c-jun kinase, NKkB or PKCθ, downstream of TLR2/4 stimulation. Effects on insulin receptor signaling are potentiated by increased infiltration of monocyte/macrophages into the tissue by release of chemokines such as MCP-1.
H4R is a high affinity receptor for histamine expressed on monocyte/macrophage populations and other hematopoietic cells. Antagonism of the H4R has been shown to reduce TLR4 signaling in vitro and to reduce TLR2 and TLR4 mediated inflammatory cytokine production in vitro and in vivo. Levels of pro-inflammatory mediators including TNF-α, IL-6 and LTB4 have been variously shown to be inhibited by H4R antagonism in TLR dependent systems. Data obtained in the context of this invention support the claim that H4R antagonists have beneficial properties towards the treatment of type 2 diabetes and related metabolic disorders through inflammation reduction.
Histamine H4 receptor antagonists have anti-inflammatory and anti-pruritic activity in animal models when given systemically. This invention also relates to the use of topical formulations of H4 receptor antagonists for the topical treatment of dermal inflammation and pruritus. The use of topical therapies for skin conditions such as urticaria and atopic dermatitis may be preferred over systemic administration due to improved safety profiles. The topical application of an H4 receptor antagonist, (5-chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (U.S. Pat. No. 6,803,362, Example 1) was tested in the context of this invention in a mouse model of pruritus. The results support the claim that topical treatment with H4 receptor antagonists have beneficial properties towards topical anti-pruritic treatment, and it is envisaged that they also have such properties regarding topical anti-inflammatory treatment. Topical formulation of such antagonists may have utility in both human and veterinary health.
Examples of textbooks on the subject of inflammation include: 1) Gallin, J. I.; Snyderman, R., Inflammation: Basic Principles and Clinical Correlates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999; 2) Stvrtinova, V., et al., Inflammation and Fever. Pathophysiology Principles of Diseases (Textbook for Medical Students); Academic Press: New York, 1995; 3) Cecil; et al. Textbook Of Medicine, 18th ed.; W.B. Saunders Co., 1988; and 4) Stedman's Medical Dictionary.
Background and review material on inflammation and conditions related with inflammation can be found in articles such as the following: Nathan, C., Nature 2002, 420(6917), 846-852; Tracey, K. J., Nature 2002, 420(6917), 853-859; Coussens, L. M., et al., Nature 2002, 420(6917), 860-867; Libby, P., Nature 2002, 420, 868-874; Benoist, C., et al., Nature 2002, 420(6917), 875-878; Weiner, H. L., et al., Nature 2002, 420(6917), 879-884; Cohen, J., Nature 2002, 420(6917), 885-891; Steinberg, D., Nature Med. 2002, 8(11), 1211-1217.
Thus, small-molecule histamine H4 receptor modulators according to this invention control the release of inflammatory mediators and inhibit leukocyte recruitment, and may be useful in treating inflammation of various etiologies, including the following conditions and diseases: inflammatory disorders, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, pruritis, and immunodeficiency disorders. Diseases, disorders and medical conditions that are mediated by histamine H4 receptor activity include those referred to herein.
Certain diamine-substituted pyridines are described in the following publications: Intl. Pat. Appl. Publ. WO 2008/122378 (UCB Pharma, Oct. 16, 2008); Intl. Pat. Appl. Publ. WO 1991/09849 (Upjohn, Jul. 11, 1991); Intl. Pat. Appl. Publ. WO 2006/063718 (Hoffmann La Roche, Jun. 22, 2006); U.S. Pat. No. 4,788,196 (Pfizer, Nov. 29, 1988); and U.S. Pat. No. 4,806,536 (Pfizer, Feb. 21, 1989).
Certain amine-substituted 2-aminopyrimidines are disclosed in the following publications: Becker, I. J. Het. Chem. 2005, 42(7), 1289-1295; Eur. Pat. Appl. No. EP 1437348 (Jul. 14, 2004); U.S. Pat. No. 3,907,801 (Sep. 23, 1975); Lespagnol, A. et al. Chim. Therap. 1971, 6(2), 105-108; Willecomme, B. Annales de Chimie 1969, 4(6), 405-428; Lespagnol, A. et al. Chim. Therap. 1965, 1, 26-31; Intl. Pat. Appl. Publ. WO 2001/62233 (Aug. 30, 2007); Intl. Pat. Appl. Publ. WO 2001/47921 (Jul. 5, 2001); U.S. Pat. Appl. Publ. US 2007/0167459 (Ono Pharmaceutical Co., Jul. 19, 2007); U.S. Pat. Appl. Publ. US 2003/0105106 (Pfizer, Jun. 5, 2003); U.S. Pat. Appl. Publ. US 2002/0147200 (Nilsson, Oct. 10, 2002); and U.S. Pat. No. 5,147,876 (Mitsui, Sep. 15, 1992).
Certain amine-substituted 2-aminopyridazines are disclosed in the following publications: Heinisch, G. Heterocycles 1999, 51(5), 1035-1050; U.S. Pat. Appl. Publ. US 2005182067 (Amgen Inc., Aug. 18, 2005) and Intl. Pat. Appl. WO 2002/022605 (Vertex Pharmaceuticals Inc., Mar. 21, 2002). Additionally, (5-piperazin-1-yl-pyridazin-3-yl)-p-tolyl-amine (CAS No. 1092336-93-0) is commercially available.
Certain substituted 2-aminopyrimidines as histamine H4 antagonists are disclosed in Intl. Pat. Appl. Publ. WO 2008/074445 (UCB Pharma, Jun. 26, 2008); WO 2005/054239 (Bayer Healthcare AG; Jun. 16, 2005) and EP 1505064 (Bayer Healthcare AG; Feb. 9, 2005; counterpart of Intl. Pat. Appl. Publ. WO 2005/014556). Substituted pyrimidines are described as histamine H4 ligands in U.S. Pat. Appl. Publ. 2007/0185075 (Pharmacia Corp.; Aug. 9, 2007), Intl. Pat. Appl. Publ. WO 2007/031529 (Palau Pharma S.A.; Mar. 22, 2007), and U.S. patent application Ser. No. 12/070,051 (Feb. 14, 2008). Additional disclosures of amino pyrimidines as histamine H4 ligands include: Intl. Pat. Appl. Publ. Nos. WO 2007/090852, WO 2007/090853, and WO 2007/090854 (Aug. 16, 2007), and EP 1767537 (Mar. 28, 2007), all reported by Cellzome Ltd., Intl. Pat. Appl. Publ. Nos. WO 2008/031556 (UCB Pharma; Mar. 20, 2008), WO 2006/050965 (Argenta; May 18, 2006), and WO 2007/072163 (Pfizer; Jun. 28, 2007).
However, there remains a need for potent histamine H4 receptor modulators with desirable pharmaceutical properties. Certain diamino-pyridine, pyrimidine and pyridazine derivatives have been found in the context of this invention to have histamine H4 receptor-modulating activity.